To achieve normal growth, development, and quality of life, individuals must maintain adequate intake of nutrition and be free from prolonged metabolic derangement. Unfortunately, people affected with either acute or chronic diseases often show disorders of nutrient balance. In some cases, a devastating state of malnutrition known as cachexia arises, brought about by a synergistic combination of a dramatic decrease in appetite and an increase in metabolism of fat and lean body mass. This combination is found in a number of disorders including cancer, cystic fibrosis, AIDS, rheumatoid arthritis, and renal failure, and is an important determinant of morbidity and mortality in these conditions. Experimental models have demonstrated the importance of cytokines in mediating illness-induced anorexia and cachexia but the neuronal systems involved in transducing this signal have not been fully defined. Work in this lab and in others has demonstrated that hypothalamic melanocortin receptors play a critical role in regulating feeding behavior, linear growth, metabolic rate, and insulin sensitivity. Stimulation of the hypothalamic melanocortin-4 receptor (MC4-R) produces relative anorexia, while prolonged antagonism of this receptor stimulates feeding and results in excessive weight gain and growth. More recently, we have been able to demonstrate that in both acute and chronic disease models, blockade of the MC4-R results in a dramatic attenuation of cachexia. We have also demonstrated that blockade of the melanocortin-3 receptor (MC3-R) leads to enhanced disease-associated cachexia whereas stimulation of the MC3-R leads to increased food intake. Current research goals fall into two general areas as described in this grant. First, we will examine the contribution and unique function the MC3-R in acute and chronic cachexia. Second, the mechanisms by which circulating cytokines and tumor-derived factors activate the hypothalamic melanocortin system will be defined. Additionally, the process of habituation to cytokine-mediated anorexia will be investigated in the context of central melanocortin function. Ultimately, this work may lead to investigation of drug therapy for this widespread medical problem.